Abstract - Project 1 Cancer is a complex, dynamical system wherein transitions across scales are non-linear. Each transition, such as the decision to express a certain gene product, is governed by a cells' content and history in response to local microenvironmental signals. Hence, cancer is an open system, as the cancer is in communication with the local environment, which can be manipulated. These microenvironments select for specific cellular phenotypes and hence, resident clades of cells are often heterogeneously distributed within sub-regions (?habitats?) of individual tumors; which can be defined by in-vivo and ex-vivo imaging. In the first PSOC period, we investigated the impact of microenvironmental factors (pH, hypoxia) on carcinogenesis itself. Herein, we change our trajectory, in concert with the entire PSOC, to investigate therapeutically actionable consequences of microenvironmental heterogeneity. Specifically, we will investigate: Aim 1, tumor oxygenation, which can be targeted with specific hypoxia-activated pro-drugs; Aim 2, metabolic heterogeneity and tumor acidity, which can be targeted by specific metabolic inhibitors and buffer therapies. Specifically we will follow promising preliminary data to investigate their impact on immune therapies; and, in response to a new trial in Project 2, Aim 3 will examine the effect of hormone-deprivation therapies on tumor-stromal interactions. Because these dynamics are complex and non-linear, we will deploy application-specific mathematical models that are developed through integration with the Bench-to-Beside Core. These models and the experiments that inform them will be iteratively improved over the course of this grant with the goal of developing novel approaches based on Evolutionary Dynamics, which can be handed off to Project 2, and integrated into novel clinical trials.